Recently employed intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is a very promising treatment for the wet form of age-related macular degeneration and diabetic retinopathy. While the therapeutic effects are positive, a major drawback is that this treatment must be repeated every four to six weeks. This is not a desirable treatment method as it is associated with several inherent complications. No currently available device can deliver anti-VEGF in a sustained manner. Hence, there is a great need for a relatively non-invasive delivery system that is more effective than the current clinical regimen. Recently, we have developed a biodegradable microspheres, thermo-responsive hydrogel ocular drug delivery system. Biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres are produced using our modified double emulsion technique providing a better microenvironment for protein-based pharmacological agents. The thermo-responsive hydrogel is a safe, effective, and injectable biomaterial that is used to encapsulate and release various agents. The hydrogel will be used to confine the microspheres to a specific delivery site. We have established both a controlled sustained release of anti-VEGF for a period of 6 months and excellent biocompatibility of the proposed drug delivery system. The overall goal of this proposal is to demonstrate the efficacy of our proposed drug delivery in both in vitro and in vivo systems and by comparing to the conventional therapy. The hypothesis is that a sustained controlled anti-VEGF release over a prolong period of ~6 months will be as effective, if not more effective, as the conventional therapy. The goal of Specific Aim 1 is to quantitatively compare the efficacy and bioactivity of the proposed drug delivery system to the conventional therapy in its ability to suppress angiogenic responses in both in vitro and in vivo models. Specific Aim 1 will be accomplished in two parts: 1a testing bioactivity of released anti-VEGF agent in an in vitro model and 1b comparing the bioactivity and treatment efficacy via time-released anti-VEGF agents to conventional treatment in a laser-induced choroidal neovascularization (CNV) rodent model. The goal of Specific Aim 2 is to measure long-term efficacy and monitor for potential side effects, if any, of the proposed drug delivery system in an in vivo model. Long-term efficacy and potential side effects will be monitored through electroretinogram (ERG) responses, scanning laser ophthalmoscope (SLO)-vascular imaging blood flow measurements, spectral- domain optical coherence tomography (SD-OCT) and histological examination (at endpoint) in both control and treated groups. Widespread clinical use of anti-VEGF necessitates a practical and effective delivery method to the posterior segment of the eye. The knowledge gained in this proposal will bring this technology one step closer to translation into the clinical practice. We believe that our drug delivery system will provide a practical and effective method to deliver anti VEGF agents. The system will have a significant impact on the current healthcare system by reducing the frequency of injections and providing benefits of sustained treatment.